Substituted 6-benzyl-4-oxopyrimidines, process for their preparation and pharmaceutical compositions containing them

ABSTRACT

The invention concerns novel substituted 6-benzyl-4-oxopyrimidines and pharmaceutically acceptable salts thereof. These compounds inhibit reverse transcriptase encoded by human immunodeficiency virus (HIV), and are useful to prevent and treat HIV infection and acquired immune deficiency syndrome (AIDS). Pharmaceutical compositions containing the compounds and a method of use of the present compounds and other agents for the treatment of AIDS and viral infection by HIV are also envisaged.

The present invention is concerned with compounds which inhibit thereverse transcriptase encoded by human immunodeficiency virus (HIV) orpharmaceutically acceptable salts thereof and are of value in theprevention of infection by HIV, the treatment of infection by HIV andthe treatment of the resulting acquired immune deficiency syndrome(AIDS). It also relates to pharmaceutical compositions containing thecompounds and to a method of use of the present compounds and otheragents for the treatment of AIDS arid viral infection by HIV.

BACKGROUND OF THE INVENTION

A retrovirus designated human immunodeficiency virus (HIV) is theetiological agent of the complex disease that includes progressivedestruction of the immune system (acquired immune deficiency syndrome;AIDS) and degeneration of the central and peripheral nervous system.

Currently available drugs for AIDS therapy are divided into two groups:those that prevent infection of target cells [nucleoside (NRTIs) andnon-nucleoside reverse transcriptase inhibitors (NNRTIs)], and thosethat prevent HIV-1-infected cells from yielding infectious viruses(protease inhibitors). Monotherapy with antiretroviral agents has shownlimited effects, very likely due to the interplay of phenomena such as:high viral loads and multiplication rates of HIV, incomplete inhibitionof viral replication and emergence of drug resistant mutants. For thisreason, combination therapies with two or more drugs have been proposedfor a more effective treatment of AIDS. Potent suppression of HIVreplication over prolonged periods has been accomplished with regimensincluding reverse transcriptase and protease inhibitors, although onstopping therapies viraemia has rapidly reappeared. In the attempt toobtain better results, research is now focused on exploiting new targetsand enhancing the activity of “old” drugs. Among the latter, NNRTspossibly endowed with better pharmacokinetic profiles, capability toinhibit clinically relevant mutants and, hopefully, to minimize HIVmultiplication are being pursued.

Compounds of the present invention aredihydro-alkyloxy-benzyl-oxopyrimidines (DABOs) which potently inhibitHIV multiplication targeting reverse transcriptase withoutbioactivation.

BRIEF DESCRIPTION OF THE INVENTION

Novel compounds of formula A:

as herein defined, are disclosed. These compounds are useful in theinhibition of HIV reverse transcriptase, the prevention of infection byHIV, the treatment of infection by HIV and in the treatment of AIDS,either as compounds, pharmaceutically acceptable salts (whenappropriate), pharmaceutical composition ingredients, whether or not incombination with other antivirals, anti-infectives, immunomodulators,antibiotics or vaccines. Methods of treating AIDS, methods of preventinginfection by HIV, and methods of treating infection by HIV are alsodisclosed.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

This invention is concerned with the compounds of formula A describedbelow, combinations thereof, or pharmaceutically acceptable saltsthereof, in the inhibition of HIV reverse transcriptase, the preventionor treatment of infection by HIV and in the treatment of the resultingacquired immune deficiency syndrome (AIDS). The compounds of thisinvention include those with structural formula A:

wherein:

X is —O, —CH₂, —CHK (wherein K is —H, —C₁₋₄ alkyl, —C₃₋₆Cycloalkyl), —S,—NK (wherein K is —H, —C₁₋₄alkyl, —C₃₋₆cycloalkyl), -aryl, -arylalkyl;

R is —H, —C₁₋₄alkyl (containing one or more of heteroatoms like O, S,N), —C₃₋₆ cycloalkyl (containing one or more of heteroatoms like O, S,N), -aryl, -arylakl, heterocycle;

Y is —H, —C₁₋₄alkyl, —C₃₋₆cycloalkyl;

Z is —H, —C₁₋₄alkyl, —C₃₋₆cycloalkyl;

R₁ is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW (wherein W is —H, —CH₃, aryl),—SW (wherein W is —H, —CH₃, -aryl);

R₂ is —H, —C₁₋₄alkyl, -halogen, —NO₂, (wherein W is —H, —CH₃, -aryl);—SW (wherein W is —H, —CH₃, -aryl);

R₃ is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW (wherein W is —H, —CH₃,-aryl); —SW (wherein W is —H, —CH₃, -aryl)

R₄ is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW (wherein W is —H, —CH₃,-aryl); —SW (wherein W is —H, —CH₃, -aryl)

R₅ is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW (wherein W is —H, —CH₃,-aryl), —SW (wherein W is —H, —CH₃, -aryl);

pharmaceutically acceptable salts or soluble derivatives thereof;

preparation process of derivatives thereof;

a method of preventing infection of HIV, or of treating infection by HIVor of treating AIDS, comprising administering to a mammal an effectiveamount of compounds claimed;

a pharmaceutical, composition useful for inhibiting HIV reversetranscriptase, comprising an effective amount of compounds claimed, anda pharmaceutically acceptable carrier;

a pharmaceutical composition useful for preventing or treating infectionof HIV or for treating AIDS, comprising an effective amount of compoundsclaimed, and a pharmaceutically acceptable carrier.

The most preferred compounds of this invention are those of table 1.

The compounds of the present invention may have asymmetric centers andoccur as racemates, racemic mixtures, individual diastereomers, orenantiomers, with all isomeric forms being included in the presentinvention.

When any variable occurs more than one time in any constituent or informula A of this invention, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

As used herein except where noted, “alkyl” is intended to include bothbranched- and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms; “Halogen” or “Hal” as usedherein, means fluoro, chloro, bromo and iodo.

As used herein, with exceptions as noted, “aryl” is intended to mean anystable monocyclic, bicyclic or tricyclic carbon ring of up to 7 membersin each ring, wherein at least one ring is aromatic. Examples of sucharyl elements include phenyl, naphthyl, tetrahydronaphthyl, biphenyl.

The term heterocycle or heterocyclic, as used herein except where notedrepresents a stable 5- to 7-membered monocyclic or stable 8- to11-membered bicyclic heterocyclic ring which is either saturated orunsaturated, and which consists of carbon atoms and from one to threeheteroatoms selected from the group consisting of N, O and S; andwherein the nitrogen and sulfur heteroatoms may optionally be oxidized,and the nitrogen heteroatom may optionally be quaternized, and includingany bicyclic group in which any of the above-defined heterocyclic ringsis fused to a benzene ring. The heterocyclic ring may be attached at anyheteroatom or carbon atom which results in the creation of a stablestructure.

The pharmaceutically-acceptable salts of the novel compounds of thisinvention that are capable of salt formation (in the form of water- oroil-soluble or dispersible products) include the conventional non-toxicsalts or the quaternary ammonium salts of these compounds, which areformed, e.g.; from inorganic or organic acids or bases.

In preferred embodiments, a compound of the present invention isadministered in combination or alternation with AZT, D4T, FTC(2′,3′-dideoxy-3′-thia-5-fluorocytidine); 3TC (Epivir, Glaxo Wellcome,Inc.), AZDU (3′-Azido-2′,3′-dideoxyuridine); 141W94 (amprenavir,GlaxoWellcome, Inc.); Viramune (nevirapine), Rescriptor (delavirdine);or DMP-266 (efavirenz). Other examples of antiviral agents that can beused in combination or alternation with the compounds disclosed hereinfor HIV therapy include DDI, DDC, Delaviridine, β-LddA,β-L-3′-azido-d5FC, carbovir, acyclovir, interferon, stavudine, CS-92(3′-azido-2′,3′-dideoxy-5-methyl-cytidine), 3′-azido nucleosides, andβ-D-dioxolane nucleosides such as β-D-dioxolanylguanine (DXG),β-D-dioxolanyl-2,6-diaminopurine (DAPD), andβ-D-dioxolanyl-6-chloropurine (ACP).

Preferred protease inhibitors include indinavir({1(1,S,2R),5(S)]-2,3,5-trideoxy-N-(2,3-dihydro-2-hydroxy-1H-inden-1-yl)-5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-4-(3-pyridinylmethyl)-1-piperazinyl]-2-(phenylmethyl)-D-erythro-pentoamidesulfate; Merck), nelfinavir (Agouron), ritonavir (Abbot), and saquinavir(Invirase; Roche).

Nonlimiting examples of other compounds that can be administered incombination or alternation with the compounds of the present inventionto augment the properties of the drug on administration includeabacavir:(1S,4R)-4-[2-amino-4-cyclopropyl-amino)-9H-purin-9-yl]-2-cyclopentene-1-methanolsuccinate (1592U89, a carbovir analog; Glaxo Wellcome); zidovudine: AZT,3′-azido-3′-deoxythymidine (Glaxo Wellcome); BILA 1906:N-{1S-[[[3-[2S-{(1,1-dimethylethyl)amino]carbonyl}-4R-]3-pyridinylmethyl)thio]-1-piperidinyl]-2R-hydroxy-1S-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl}-2-quinolinecarboxamide(Bio Mega/Boehringer-Ingelheim); BILA 2185:N-(1,1-dimethylethyl)-1-[2S-[[2-2,6-dimethylphenoxy)-1-oxoethyl]amino]-2R-hydroxy-4-phenylbutyl]4R-pyridinylthio)-2-piperidinecarboxamide(Bio Mega/Boehringer-Ingelheim); BM+51.0836:triazoloisoindolinonederivative; BMS 186,318: aminodiol derivative HIV-1 protease inhibitor(Bristol-Myers-Squibb); d4API:9-[2,5-dihydro-5-(phosphonomethoxy)-2-furanel]adenine (Gilead);stavudine: d4T, 2′,3′-didehydro-3′-deoxythymidine(Bristol-Myers-Squibb); efavirenz: DMP-266, a1,4-dihydro-2H-3,1-benzoxazin-2-one; HBY097:S-4-isopropoxycabonyl-6-methoxy-3-(methylthio-methyl)-3,4-dihydroquinoxalin-2(1H)-thione;HEPT: 1-[(2-hydroxyethoxy)methyl]6-(phenylthio)thymine; KNI-272:(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid-containing tripeptide;L-697,593; 5-ethyl-6-methyl-3-(2-phthalimido-ethyl)pyridin-2(1H)-one;L-735,524: hydroxy-aminopentane amide HIV-1 protease inhibitor (Merck);L-697,661:3-{[(-4,7-dichloro-1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methylpyridin-2(1H)-one;L-FDDC: (−)-β-L-5-fluoro-2′,3′-dideoxycytidine; L-FDOC:(−)-β-L-5-fluoro-dioxolane cytosine;6-benzyl-1-ethoxymethyl-5-isopropyluracil (I-EBU; Triangle/Mitsubishi);nevirapine:11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyridol[3,2-b:2′,3′-e]diazepin-6-one(Boehringer-Ingelheim); PFA: phosphonoformate (foscarnet; Astra); PMEA:9-(2-phosphonylmethoxyethyl) adenine (Gilead); PMPA:(R)-9-(2-phosphonyl-methoxypropyl)adenine (Gilead); Ro 31-8959:hydroxythethylamine derivative HIV-1 protease inhibitor (Roche);RPI-3121: peptidyl protease inhibitor,1-[(3s)-3-(n-alpha-benzyloxycarbonyl)-1-asparginyl)-amino-2-hydroxy-4-phenylbutyryl]-n-tert-butyl-1-prolineamide; 2720:6-chloro-3,3-dimethyl-4-(isopropenyloxycarbonyl)-3,4-dihydro-quinoxalin-2(1H)thione;SC-52151: hydroxyethylurea isostere protease inhibitor (Searle);SC-55389A: hydroxyethyl-urea isostere protease inhibitor (Searle); TIBOR82150:(+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione(Janssen); TIBO 82913:(+)-(5S)-4,5,6,7,-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,jk]-[1,4]benzodiazepin-2(1H)-thione(Janssen); TSAO-m3T:[2′,5′-bis-O-(tert-butyldimethylsilyl)-3′-spiro-5′-(4′-amino-1′,2′-oxathiole-2′,2′-dioxide)]-β-D-pentofuranosyl-N3-methylthymine;U90152:1-[3-[(1-methylethyl)-amino]2-pyridinyl]-4-[[5-[(methylsulphonyl)-amino]-1H-indol-2yl]carbonyl]piperazine;UC: thiocarboxanilide derivatives (Uniroyal);UC-781=N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothioamide;UC-82=N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-thiophenecarbothioamide;VB 11,328: hydroxyethylsulphonamide protease inhibitor (Vertex); VX-478:amprenavir, 141W94, hydroxyethylsulphonamide protease inhibitor(Vertex/Glaxo Wellcome); XM 323: cyclic urea protease inhibitor (DupontMerck), delaviridine (Pharmacia Upjohn), famciclovir, gancyclovir, andpenciclovir. In another embodiment, a compound of the present inventionis administered in combination with LG1350, which has the followingstructure.

Anhydrous pyridine (400 mmoles, 32.5 ml) was added with stirring undernitrogen atmosphere into an ice-cooled solution of2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrurm's acid) (165 mmoles, 23.75g) in anhydrous dichloromethane (50 ml). The resulting solution wastreated, over a 2 h period at 0° C. under nitrogen atmosphere, with asolution of crude arylacetyl chloride in anhydrous dichloromethane (50ml). Arylacetyl chloride was prepared before use by refluxing the properarylacetic acid (43.2 mmoles) with thionyl chloride (21.3 ml) undernitrogen atmosphere for 2 h. Then, the mixture was stirred for 2 h atroom temperature, poured into crushed ice and treated with 2N HCl (100ml). The organic layer was separated and the aqueous solution wasextracted twice with dichloromethane (25 ml). The organic phase and theextracts were combined, washed with brine, dried and evaporated. Thesolid residue was dissolved in anhydrous methanol (250 ml) and thesolution was refluxed for 20 h. After cooling, metal sodium (0.16g-atoms, 3.68 g) was carefully added and the mixture was stirred untildissolution was complete. Alkyl halide (160 mmoles) was dropped into thesolution and the resulting mixture was heated at reflux for 4-12 h.After cooling, the solvent was removed and the residue treated withwater (200 ml) and extracted with chloroform (3×100 ml). The organiclayer was washed with brine (2×100 ml), dried and evaporated to give thedesired compound, which was purified by passing through a silica gelcolumn (chloroform as eluent).

In the above reaction, arylacetic acid (Scheme “A”) or arylacetylchloride can be replaced with the corresponding 1-arylacetylimidazolide(Scheme “B”) or with arylacetylethoxycarbonylanhydride, whereas theMeldrum's acid can be replaced with ethyl acetylacetate, ethylalkylmalonate or ethyl alkylmalonate potassium salt, to give the properethyl arylacetylalkylacetates in high yields.

Preparation of Compounds (I) With X=O (Scheme A)

The proper methyl arylacetylalkylacetate (10 mmoles) in methanol (50 ml)was added to a well-stirred suspension of O-methylisourea hydrogensulphate (15 mmoles, 2.58 g) and calcium hydroxide (16 mmoles, 1.18 g)in water (50 ml). The resulting mixture was stirred at room temperaturefor 72 h, then concentrated, made acid (pH 5) with 0.5N acetic acid andextracted with ethyl acetate (3×50 ml). The combined organic extractswere washed with brine (100 ml), dried and evaporated to dryness. Theresidue was purified by crystallization from the proper solvent yieldingpure 5-alkyl-6-benzyl-3,4-dihydro-2-methoxypyrimidin-4-one. Thiscompound was then refluxed with the proper potassium alkoxide (100mmoles of potassium metal in 20-30 ml of alcohol freshly distilled onsodium metal) under nitrogen atmosphere until starting materialdisappeared at the TLC control. After cooling, the mixture wasconcentrated, made acid (pH 5) with 0.5N acetic acid and extracted withethyl acetate (3×50 ml). The combined extracts were washed once withbrine (100 ml), dried and evaporated to give the required2-alkoxy-5-alkyl-6-benzyl-3,4-dihydropyrimidin-4-one derivative, whichwas recrystallized from a suitable solvent or purified by columnchromatography (silica gel; ethyl acetate:chloroform 1:1). Physical andchemical data of representative compounds of the invention are reportedin table 1; cytotoxicity and anti-HIV-1 activity data are reported intable 2.

Preparation of Compounds (I) with X=S

The proper ethyl arylacetylalkylacetate (31.5 mmole as successivelyadded to a stirred solution of sodium metal (0.063 g-atoms) in 50 mL ofabsolute ethanol (50 ml) thiourea (43 mmoles). The mixture was heatedwhile stirring at reflux for 5 h. After cooling, the solvent wasdistilled in vacuo at 40-50° C. until dryness and the residue wasdissolved in water (200 mL) and made acid (pH 5) with 0.5N acetic acid.The resulting precipitate (the crude 2-thiouracil derivative) wasfiltered under reduced pressure, washed with diethyl ether, vacuum driedat 80° C. for 12 h and then crystallized from the proper solvent.

Then, according to method A, iodomethane (8 mmoles, 1.13 g) was added toa suspension containing the proper 2-thiouracil derivative (4 mmoles) inanhydrous N,N-dimethylformamide (2 ml), and the resulting mixture wasstirred at room temperature until the starting material disappeared atthe TLC control (silica gel; n-hexane: ethyl acetate:methanol 12:3:1).Then the reaction content was poured on cold water (100 mL) andextracted with ethyl acetate (3×50 ml). The organic layers werecollected, washed with a sodium thiosulfate solution (100 ml), brine(3×50 ml), dried and evaporated to furnish the crude5-alkyl-6-benzyl-3,4-dihydro-2-methylthiopyrimidin-4-one (2) as a solidpurified by crystallization.

Alternatively, according to methods B and C, potassium carbonate (4.2mmoles) and the proper alkyl halide (4.4 mmoles) were added to asuspension containing 2-thiouracil derivative (4 mmoles) in anhydrousN,N-dimethylformamide (2 ml). The resulting mixture was stirred at roomtemperature (method B) or at 80° C. (method C) until starting materialdisappeared at the TLC control (silica gel; n-hexane:ethylacetate:methanol 12:3:1). Then the reaction content was poured on coldwater (200 mL), made acid (pH 5) with 0.5N acetic acid and extractedwith ethyl acetate (3×50 ml). The organic layers were collected, washedwith a sodium thiosulfate solution (100 ml), brine (100 ml), dried andevaporated to furnish5-alkyl-6-benzyl-3,4-dihydro-2-methylthiopyrimidin-4-ones (3) and (4) ascrude material which was then purified by column chromatography onsilica gel (eluent: n-hexane:ethyl acetate:methanol 12:3:1) followed bycrystallization. Physical and chemical data of representative compoundsof the invention are reported in table 1. Cytotoxicity and anti-HIV-1activity in vitro are reported in table 2.

Title derivatives were prepared according to the procedure described forthe synthesis of compounds with X=S (I), using ethylarylacetylalkylacetates and guanidine [2-amino-6-benzylpyrimidin-4-ones(5)] as starting materials. 2-Alkylaminoderivatives (6) were synthesizedby heating the previously reported5-alkyl-6-benzyl-3,4-dihydro-2-methylthio pyrimidin-4-ones with 20-30 mlof proper amine in a sealed tube at 170° C. for 24 h. Physical andchemical data of some compounds (6) are reported in table 1.Cytotoxicity and anti-HIV-1 activity in vitro are reported in table 2.The compounds of the present invention are useful in the inhibition ofHIV reverse transcriptase, the prevention or treatment of infection bythe human immunodeficiency virus (HIV) and the treatment of consequentpathological conditions such as AIDS. Treating AIDS or preventing ortreating infection by HIV is defined as including, but not limited to,treating a wide range of states of HIV infection: AIDS, ARC (AIDSrelated complex), both symptomatic and asymptomatic, and actual orpotential exposure to HIV. For example, the compounds of this inventionare useful in treating infection by HIV after suspected past exposure toHIV by, e.g., blood transfusion, organ transplant, exchange of bodyfluids, bites, accidental needle stick, or exposure to patient bloodduring surgery.

The compounds of this invention are also useful in the preparation andexecution of screening for antiviral compounds. For example, thecompounds of this invention are useful for isolating enzyme mutants,which are excellent screening tools for more powerful antiviralcompounds. Furthermore, the compounds of this invention are useful inestablishing or determining the binding site of other antiviral to HIVreverse transcriptase e.g., by competitive inhibition. Thus thecompounds of this invention are commercial products to be sold for thesepurposes. For inhibition of HIV reverse transcriptase, the prevention ortreatment of infection by HIV and the treatment of AIDS or ARC, thecompounds of the present invention may be administered orally,parenterally (including subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques), byinhalation spray, or rectally, in dosage unit formulations containingconventional non toxic pharmaceutically-acceptable carriers, adjuvantsand vehicles. Thus, in accordance with the present invention there isfurther provided a method of treating and a pharmaceutical compositionfor treating HIV infection and AIDS. The treatment involvesadministering to a patient in need of such treatment a pharmaceuticalcomposition comprising a pharmaceutical carrier and a therapeuticallyeffective amount of a compound of the present invention. Thesepharmaceutical compositions may be in the form of orally administrablesuspensions or tablets; nasal sprays: sterile injectable preparations,for example, as sterile injectable aqueous or oleagenous suspensions orsuppositories.

When administered orally as a suspension, these compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may contain microcrystalline cellulose for impartingbulk, alginic acid or sodium alginate as a suspending agent,methylcellulose as a viscosity enhancer, and sweetners/flavoring agentsknown in the art. As immediate release tablets, these compositions maycontain microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants known in the art.

When administered by nasal aerosol or inhalation, these compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other solubilizing or dispersingagents known in the art.

The injectable solutions or suspensions may be formulated according toknown art, using suitable non toxic, parenterally acceptable diluents orsolvents, such as mannitol, 1,3-butanediol, water. Ringer's solution orisotonic sodium chloride solution, or suitable dispersing or wetting andsuspending agents, such as sterile, bland, fixed oils, includingsynthetic mono- or diglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, thesecompositions may be prepared by mixing the drug with a suitablenon-irritating excipient; such as cocoa buffer, synthetic glyceride,esters or polyethylene glycols, which are solid at ordinarytemperatures, but liquidity and/or dissolve in the rectal cavity torelease the drug.

The compounds of this invention can be administered orally to humans ina dosage range of 1 to 75 mg/kg body weight. One preferred dosage rangeis 1 to 50 mg/kg body weight orally. Another preferred dosage range is 5to 75 mg/kg body weight orally. It will be understood, however, that thespecific dose level and frequency of dosage for any particular patientmay be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular condition, and the hostundergoing therapy.

The present invention is also directed to combinations of the HIVreverse transcriptase inhibitor compounds with one or more agents usefulin the treatment of AIDS. The compounds of this invention can beadministered in combination with other compounds that are HIV reversetranscriptase inhibitors, and/or with compounds that are HIV proteaseinhibitors. When used in a combination treatment with compounds of theinstant invention, dosage levels of HIV protease inhibitors of the orderof 1 to 25 or 50 grams-per-day are useful in the treatment or preventionof the above-indicated conditions, with oral doses two-to-five timehigher. For example, infection by HIV is effectively treated by theadministration of from 5 to 25 milligrams of the HIV protease inhibitorper kilogram of body weight from one to three times per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy. Dosages ofHIV reverse transcriptase inhibitors, when used in a combinationtreatment with compounds of the present invention, are comparable tothose dosages specified above for the present compounds. It will beunderstood that the scope of combinations of the compounds of thisinvention with AIDS antivirals includes any combination with anypharmaceutical composition useful for the treatment of AIDS.

ANTIVIRAL ASSAY PROCEDURES

Compounds. Compounds were solubilized in DMSO at 200 mM and then dilutedinto culture medium.

Cells and viruses. MT-4, C8166, H9/IIIB and CEM cells were grown at 37°C. in a 5% CO₂ atmosphere in RPMI 1640 medium, supplemented with 10%fetal calf serum (FCS), 100 UI/mL penicillin and 100 μg/mL streptomycin.Cell cultures were checked periodically for the absence of mycoplasmacontamination with a MycoTect Kit (Gibco). Human immunodeficiency virustype-1 (HIV-1, III_(B) strain) was obtained from supernatants ofpersistently infected H9/III_(B) cells. HIV-1 stock solution had atitres of 4.5×10⁶ 50% cell culture infectious dose (CCID₅₀)/ml.

HIV titration. Titration of HIV was performed in C8166 cells by thestandard limiting dilution method (dilution 1:2, four replica wells perdilution) in 96-well plates. The infectious virus titre was determinedby light microscope scoring of cytopathicity after 4 days of incubationand the virus titres were expressed as CCID₅₀/mL.

Anti-HIV assays. Activity of the compounds against HIV-1 and HIV-2multiplication in acutely infected cells was based on the inhibition ofvirus-induced cytopathicity in MT-4 and C8166 cells, respectively.Briefly, 50 μL of culture medium containing 1×10⁴ cells were added toeach well of flat-bottom microtiter trays containing 50 μl of culturemedium with or without various concentrations of the test compounds.Then 20 μL of an HIV suspension containing 100 CCID₅₀ were added. Aftera 4-day incubation at 37° C., the number of viable cells was determinedby the 3-(4,5-dimethylthiazol-1-yl)-2,5-diphenyltetrazolium bromide(MTT) method. Cytotoxicity of the compounds was evaluated in parallelwith their antiviral activity. It was based on the viability ofmock-infected cells, as monitored by the MTT method.

RT assays. Assays were performed as follows. Briefly, purified rRT wasassayed for its RNA-dependent polymerase-associated activity in a 50 μLvolume containing: 50 mM TrisHCl (pH 7.8). 80 mM KCIl, 6 mM MgCl2, 1 mMDTT. 0.1 mg/mL BSA, 0.3 OD₂₆₀ unit/mL template:primer[poly(rC)-oligo(dG)12-18] and 10 μM [³H]dGTP (1 Ci/mmol). Afterincubation for 30 min at 37° C., the samples were spotted on glass fiberfilters (Whatman GF/A), and the acid-insoluble radioactivity wasdetermined.

EXAMPLES2-Cyclopentylthio-6-(2,6-difluorophenylmethyl)-3,4-dihydrogyrimidin-4-(3H)-one(MC867)

A mixture of6-(2,6-difluorophenylmethyl)-1,2,3,4-tetrahydro-2-thiopyrimidin-4(3H)-one(0.16 g, 0.65 mmol; prepared as reported in scheme B), cyclopentylbromide (0.11 g, 0.08 mL., 0.71 mmol) and potassium carbonate (0.09 g,0.65 mmol) in 1 mL of anhydrous DMF was stirred at room temperature for24 h. After treatment with cold water (200 mL), the solution wasextracted with ethyl acetate (3×50 mL). The organic layers werecollected, washed with brine (3×50 mL), dried and evaporated to furnishcrude MC867, which was purified by chromatography on silica gel column(eluent: n-hexane/ethyl acetate/methanol 12/3/1).

Yield (%): 45; mp (° C.): 168-169; recrystallization solvent:cyclohexane; formula (molecula-weight): C₁₆H₁₆F₂N₂OS (322.37).

2-Cyclopenlythio-6-(2,6-diflurophenymethyl)-3,4-dihydro-5-methylpyrimidin-4-(3H)-one(MC922)

The synthesis of MC922 was accomplished according to the above reportedprocedure starting from6-(2,6-difluorophenylmethyl)-5-methyl-1,2,3,4-tetrahydro-2-thiopyrimidin-4-(3H)-one(see scheme B).

Yield (%): 54; mp (° C.): 192-193; recrystallization solvent:cyclohexane; formula (molecular weight): C₁₇H₁₈F₂N₂OS (336.40).

2-Cyclopentylthio-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydropyrimidin-4-(3H)-one(MC1008)

The synthesis of MC1008 was accomplished according to the above reportedprocedure starting from6-[1-(2,6-difluorophenyl)ethyl]-1,2,3,4-tetrahydro-2-thiopyrimidin-4-(3H)-one(see scheme B).

Yield (%): 54; mp (° C.): 165.5-166.5; recrystallization solvent:cyclohexane; formula (molecular weight): C₁₇H₁₈F₂N₂OS (336.40).

2-Cyclopentylthio-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methylpyrimidin4(3H)-one(MC1047)

The synthesis of MC1047 was accomplished according to the above reportedprocedure, starting from6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-1,2,3,4-tetrahydro-2-thiopyrimidin-4(3H)-one(see scheme B).

Yield (%): 60; mp (° C.): 196-197; recrystallization solvent:cyclohexane; formula (molecular weight): C₁₈H₂₀F₂N₂OS (350.43).

6-(2,6-Difluorophenymethyl)-3,4-dihydro-2-(methylthiomethyl)thiopyrimidin-4-(3H)-one(MC1161)

The synthesis of MC1161 was accomplished according to the above reportedprocedures, starting from6-(2,6-difluorophenylmethyl)-1,2,3,4-tetrahydro-2-thiopyrimidin-4(3H)-one(see scheme B) and chloromethyl methyl sulfide.

Yield (%): 72; mp (° C.): 159-160; recrystallization solvent:benzene/cyclohexane; formula (molecular weight): C₁₃H₁₂F₂N₂OS₂ (314.37).

6-(2,6-Difluorophenylmethyl)-3,4-dihydro-5-methyl-2-(methylthiomethylthiopyrimidin-4(3H)-one(MC1162)

The synthesis of MC1162 was accomplished according to the above reportedprocedure, starting from6-(2,6-difluorophenylmethyl)-5-methyl-1,2,3,4-tetrahydro-2-thiopyrimidin4(3H)-one (see scheme B) and chloromethyl methyl sulfide.

Yield (%): 70; mp (° C.): 183-184; recrystallization solvent:benzene/cyclohexane; formula (molecular weight): C₁₄H₁₄F₂N₂OS₂ (328.39).

6-(2,6-Difluorophenylmethyl)-3,4-dihydro-5-(1-methylethyl)-2-(methylthiomethyl))thiopyrimidin-4-(3H)-one MC1145)

The synthesis of MC1145 was accomplished according to the above reportedprocedure, starting from6-(2,6-difluorophenylmethyl)-5-(1-methylethyl)-1,2,3,4-tetrahydro-2-thiopyrimidin-4(3H)-one(see scheme B) and chloromethyl methyl sulfide.

Yield (%): 62; mp (° C.): 158.5-160; recrystallization solvent:cyclohexane; formula (molecular weight): C₁₆H₁₈F₂N₂OS₂ (356.45).

2-Cyclopenltylamino-6-(2,6-difluorophenylmethyl)-3,4-dihydropyrimidin-4-(3H)-one(MC1022)

Cyclopentylamine (10 mL) was heated while stirring with6-(2,6-difluorophenylmethyl)-3,4-dihydro-2-methylthiopyrimidin-4-(3H)-one(0.30 g, 1.12 mmol; prepared as reported in scheme B or C) in a sealedtube at 160° C. for 10 h. After cooling, the mixture was diluted withwater (200 mL) and extracted with ethyl acetate (3×50 mL). The organiclayers were collected, washed with brine (3×50 mL), dried and evaporatedto furnish crude MC1022, which was purified by chromatography on silicaget column (eluent: ethyl acetate/chloroform 1/1).

Yield (%): 74: mp (° C.):—(oil); formula (molecular weight): C₁₆H₁₇F₂N₃O(305.33).

2-Cyclopentylamino-6-(2,6-difluorophenylmethyl)-3,4-dihydro-5-methylpyrimidin-4-one(MC1050)

The synthesis of MC1050 was accomplished according to the above reportedprocedure, starting from6-(2,6-difluorophenylmethyl)-3,4-dihydro-5-methyl-2-methylthiopyrimidin-4(3H)-one(see scheme B or C).

Yield (%): 60:. mp (° C.): 115-117; recrystallization solvent:n-hexane/cyclohexane; formula (molecular weight): C₁₇H₁₉F₂N₃O (319.35).

2-Cyclopentylamino-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydropyrimidin-4-(3H)-one(MC1048)

The synthesis of MC1048 was accomplished according to the above reportedprocedure, starting from6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-2-methylthiopyrimidin-4(3H)-one(see scheme B or C).

Yield (%): 48: mp (° C.):—(oil); formula (molecular weight) C₁₇H₁₉F₂N₃O(319.35).

2-Cyclopentylamino-6-[1-(2,6-difluorophenylethyl]-3,4-dihydro-5-methylpyrimidin-4-(3H)-one(MC1129)

The synthesis of MC1129 was accomplished according to the above reportedprocedure, starting from6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methyl-2-methylthiopyrimidin-4(3H)-one(see scheme B or C).

Yield (%): 38; mp (° C.):—(oil); formula (molecular weight): C₁₈H₂₁F₂N₃O(333.38).

6-(2,6-Difluorophenylmethyl)-3,4-dihydro-2-(4-thiomorpholin-1-yl)pyrimidin-4-(3H)-one(MC1193)

The synthesis of MC1193 was accomplished according to the above reportedprocedure, starting from thiomorpholine and6-(2,6-difluorophenylmethyl)-3,4-dihydro-2-methylthiopyrimidin-4(3H)-one(see scheme B or C).

Yield (%) 78, mp (° C.): 233-234; recrystallization solvent:acetonitrile; formula (molecular weight): C₁₅H₁₅F₂N₃OS (323.36).

6-(2,6-Difluorophenylmethyl)-3,4-dihydro-2-N,N-dimethylaminopyrimidin-4-(3H)-one(MC1182)

To a stirred solution of sodium metal (0.14 g, 6.3 mg-atoms) in absoluteethanol (50 mL) 1,1-dimethylguanidine sulfate (1.17 g, 4.3 mmol) andethyl 4-(2,6-difluorophenyl)acetylacetate (0.76 g, 3.15 mmol) weresuccessively added. The mixture was heated while stirring at reflux for8 h. After cooling, the solvent was distilled in vacuo at 40-50° C.until dryness and the residue was dissolved in water (200 mL) and madeacid (pH 5) with 0.5N acetic acid. The resulting precipitate (the crudeisocytosine derivative) was filtered under reduced pressure, washed withdiethyl ether, vacuum dried at 80° C. for 12 h and then crystallizedfrom benzene/cyclohexane (see scheme C starting from ethyl4-(2,6-difluorophenyl)acetylacetate and replacing guanidinehydrochloride with 1,1-dimethylguanidine sulfate).

Yield (%): 88; mp (° C.): 210-211: recrystallization solvent:benzene/cyclohexane; formula (molecular weight): C₁₃H₁₃F₂N₃O (265.26).

TABLE 1 Physical and Chemical Data of MC Compounds

Compd. X Y Z R R¹ R² R³ R⁴ R⁵ m.p., ° C. MC 507 O H H 2,5-Me₂-c-hex H HH H H 130-132 MC 508 O H H 4,5-Me₂-c-hex H H H H H 132-134 MC 512 O H H3,5-Me₂-c-hex H H H H H 178-181 MC 531 O Me H 2,5-Me₂-c-hex H H H H H196-198 MC 1114 O H H Sec-but F H H H F 87-88 MC 1103 O H H c-pent F H HH F 183.5-184.5 MC 843 S H H benzyloxymeth H H H H H 181-183 MC 796 S HPh Sec-but H H H H H 157-158 MC 890 S H Me iso-prop H H H H H 118-119 MC892 S H Me c-pent H H H H H 95-96 MC 898 S H Me c-hex H H H H H 142-143MC 899 S H Et iso-prop H H H H H 144-145 MC 900 S H Et c-pent H H H H H168-169 MC 903 S H Et c-hex H H H H H 175.5-176.5 MC 806 S H H Sec-butMe H H H H 118-119 MC 842 S H H c-pent Me H H H H 142-144 MC 809 S H HSec-but H H Me H H 107.5-108.5 MC 817 S H H Sec-but NO₂ H H H H148.0-148.5 MC 897 S H H Sec-but H NO₂ H H H 127-128 MC 863 S H HSec-but H H NO₂ H H 128-130 MC 854 S H H Sec-but Cl H H H H 120-121 MC857 S H H Sec-but H Cl H H H 98-99 MC 859 S H H Sec-but H H Cl H H125-126 MC 880 S H H Sec-but F H H H H 106-107 MC 884 S H H Sec-but H FH H H 96-97 MC 889 S H H Sec-but H H F H H 98-99 MC 825 S H H Sec-butNH₂ H H H H 143-144 MC 960 S H H Sec-but H H NH₂ H H 128-130 MC 868 S HH Sec-but CF₃ H H H H 125-126 MC 959 S H H Sec-but H H CF₃ H H 144-145MC 952 S H H Sec-but OMe H H H H 123-124 MC 957 S H H Sec-but H OMe H HH 78-80 MC 964 S H H Sec-but H H OMe H H 112-113 MC 1041 S H H Sec-but HF H H H 122-123 MC 1042 S H H Sec-but H Me H H H 119-120 MC877 S H H MeCl H H H Cl 237-238 MC878 S H H iso-prop Cl H H H Cl 230-231 MC886 S H Hn-but Cl H H H Cl 153-154 MC885 S H H iso-but Cl H H H Cl 143.5-144.5MC815 S H H sec-but Cl H H H Cl 183-184 MC888 S H H c-pent Cl H H H Cl185-186 MC891 S H H c-hex Cl H H H Cl 200-201 MC871 S H H Me F H H H F197-198 MC860 S H H iso-prop F H H H F 174-175 MC872 S H H n-but F H H HF 126-127 MC866 S H H iso-but F H H H F 136-137 MC848 S H H sec-but F HH H F 149-150 MC867 S H H c-pent F H H H F 168-169 MC870 S H H c-hex F HH H F 164-165 MC1001 S H Me iso-prop Cl H H H Cl   196-196.5 MC996 S HMe c-pent Cl H H H Cl 181-182 MC1016 S H Me c-hex Cl H H H Cl 211-212MC1000 S H Et iso-prop Cl H H H Cl 166-168 MC1002 S H Et c-pent Cl H H HCl 168-169 MC1003 S H Et c-hex Cl H H H Cl 198-199 MC1007 S H Meiso-prop F H H H F 155-156 MC1044 S H Me iso-but F H H H F 159-160MC1045 S H Me n-but F H H H F 149-150 MC1110 S H Me sec-but F H H H F133-134 MC1008 S H Me c-pent F H H H F 165.5-166.5 MC1013 S H Me c-hex FH H H F 206-207 MC1005 S H Et iso-prop F H H H F 149-150 MC1006 S H Etc-pent F H H H F 141-143 MC1014 S H Et c-hex F H H H F 154-155 MC971 S HMe iso-prop CH═CH—CH═CH H H H 161-162 MC972 S H Me c-pent CH═CH—CH═CH HH H 140-141 MC974 S H Me c-hex CH═CH—CH═CH H H H 177-178 MC969 S H Etiso-prop CH═CH—CH═CH H H H 163-164 MC973 S H Et c-pent CH═CH—CH═CH H H Hoil MC975 S H Et c-hex CH═CH—CH═CH H H H 126-127 MC844 S Me H sec-but MeH H H H 177-178 MC845 S Me H sec-but H H Me H H 127-128 MC925 S Me Hsec-but H NO₂ H H H 163-164 MC924 S Me H sec-but H H NO₂ H H 178-180MC909 S Me H sec-but Cl H H H H 170-171 MC910 S Me H sec-but H Cl H H H145-146 MC911 S Me H sec-but H H Cl H H 163-165 MC913 S Me H sec-but F HH H H 120.5-121.5 MC918 S Me H sec-but H F F H H 146-147 MC919 S Me Hsec-but H H H H H 154-155 MC912 S Me H Me Cl H H H Cl 206-261 MC914 S MeH iso-prop Cl H H H Cl 241-242 MC920 S Me H n-but Cl H H H Cl 179-180MC916 S Me H iso-but Cl H H H Cl 208-209 MC850 S Me H sec-but Cl H H HCl 204-205 MC915 S Me H c-pent Cl H H H Cl 252-253 MC917 S Me H c-hex ClH H H Cl 237-238 MC869 S Me H Me F H H H F 218.5-219.5 MC881 S Me Hiso-prop F H H H F 164-165 MC905 S Me H n-but F H H H F 178-179 MC921 SMe H iso-but F H H H F 161-162 MC849 S Me H sec-but F H H H F 128-129MC922 S Me H c-pent F H H H F 192-193 MC923 S Me H c-hex F H H H F191-192 MC1060 S Me Me Me F H H H F 202-203 MC1109 S Me Me sec-but F H HH F 135-136 MC1047 S Me Me c-pent F H H H F 196-197 MC798 S Et H sec-butH H H H H 140-141 MC1037 S Et H iso-prop F H H H F 174-175 MC1038 S Et Hsec-but F H H H F 150-151 MC804 S Et H sec-but CH═CH—CH═CH H H H198.5-199.5 MC1039 S i-pro H iso-prop F H H H F 167-168 MC852 S allyl Hsec-but H H H H H 127.5-128.5 MC856 S n-pro H sec-but H H H H H 108-109MC834 S n-but H sec-but H H H H H oil MC1119 NH H H ethyl F H H H F138-140 MC1078 NH H H n-prop F H H H F 136-137 MC979 NH H H iso-prop F HH H F 150-151 MC980 NH H H c-prop F H H H F 183-184 MC1077 NH H H n-butF H H H F 130-131 MC945 NH H H sec-but F H H H F 140-141 MC1043 NH H HMeOethyl F H H H F 120-121 MC1022 NH H H c-pent F H H H F oil MC1049 NHH H c-hex F H H H F 143-144 MC1048 NH H Me c-pent F H H H F oil MC1118NH Me H iso-prop F H H H F 165-166 MC1130 NH Me H sec-but F H H H F oilMC1050 NH Me H c-pent F H H H F 115-117 MC1105 NH Me H benzyl F H H H F182-183 MC1129 NH Me Me c-pent F H H H F oil MC1167 NH H H Me F H H H F202-203 MC1168 NH Me H Me F H H H F 210-211 MC1186 NH Me H n-prop F H HH F 156-157 MC1185 NH Me H n-but F H H H F 192-193 MC1178 NH H Me Me F HH H F 145-146 MC1190 NH H Me n-prop F H H H F oil MC1191 NH H Meiso-prop F H H H F oil MC1189 NH H Me n-but F H H H F oil MC1192 NH H Mesec-but F H H H F oil MC1180 NH H Me c-hex F H H H F oil MC1170 NH Me MeMe F H H H F 193-194 MC1187 NH Me Me n-but F H H H F oil MC1181 NH Me Mec-hex F H H H F oil MC1182 N H H Me₂ F H H H F 210-211 MC1183 N H HMe-piperaz F H H H F 195-196 MC1188 N H H morph F H H H F 215-216 MC1193N H H thiomorph F H H H F 233-234 MC1194 N H H piperid F H H H F 209-210MC1196 N H H pyrrolid F H H H F 233-234 MC1202 N H H Et₂ F H H H F159-160 MC1204 N H H (n-prop)₂ F H H H F 111-112 MC1195 N Me H Me₂ F H HH F 237-238 MC1203 N Me H Me-piperaz F H H H F 235-236 MC1205 N Me Hmorph F H H H F 244-245 MC1206 N Me H thiomorph F H H H F 255-256 MC1137S Me Me iso-prop F H H H F 177-178 MC1175 S Me Me n-but F H H H F122-123 MC1153 S Me Me iso-but F H H H F 152-153 MC1174 S Me Me c-hex FH H H F 208-209 MC1161 S H H MeSMe F H H H F 159-160 MC1162 S Me H MeSMeF H H H F 183-184 MC1157 S Et H MeSMe F H H H F 153-154 MC1145 S i-pro HMeSMe F H H H F 158.5-160   MC1140 S H H MeSMe H H H H H 117.5-118  Compd. Recryst. Solvent % yield Formula ^(a) MC 507 Petrol.Ether/diethyl ether 22 C₁₉H₂₄N₂O₂ MC 508 Petrol. Ether/diethyl ether 28C₁₉H₂₄N₂O₂ MC 512 Petrol. Ether/diethyl ether 12 C₁₉H₂₄N₂O₂ MC 531Petrol. Ether/diethyl ether 18 C₂₀H₂₆N₂O₂ MC 1114 Petrol. Ether/diethylether 28 C₁₅H₁₆F₂N₂O₂ MC 1103 Benzene 52 C₁₆H₁₆F₂N₂O₂ MC 843Cyclohexane/benzene 38 C₁₉H₁₈N₂O₂S MC 796 n-hexane/cyclohexane 78C₂₁H₂₂N₂OS MC 890 n-hexane 88 C₁₅H₁₈N₂OS MC 892 n-hexane 65 C₁₇H₂₀N₂OSMC 898 n-hexane 59 C₁₆H₂₂N₂OS MC 899 Cyclohexane 85 C₁₆H₂₀N₂OS MC 900Cyclohexane 69 C₁₈H₂₂N₂OS MC 903 Cyclohexane 60 C₁₉H₂₄N₂OS MC 806n-hexane/cyclohexane 67 C₁₆H₂₀N₂OS MC 842 Cyclohexane 61 C₁₇H₂₀N₂OS MC809 n-hexane 56 C₁₆H₂₀N₂OS MC 817 Cyclohexane/benzene 68 C₁₅H₁₇N₃O₃S MC897 Cyclohexane/benzene 54 C₁₅H₁₇N₃O₃S MC 863 Petrol. Ether/diethylether 100 C₁₅H₁₇N₃O₃S MC 854 n-hexane/cyclohexane 58 C₁₅H₁₇N₃O₃S MC 857Cyclohexane 92 C₁₅H₁₇N₃O₃S MC 859 Cyclohexane 74 C₁₅H₁₇ClN₂OS MC 880n-hexane/cyclohexane 68 C₁₅H₁₇ClN₂OS MC 884 Cyclohexane 67 C₁₅H₁₇FN₂OSMC 889 n-hexane 94 C₁₅H₁₇FN₂OS MC 825 Cyclohexane/benzene 74 C₁₅H₁₉N₂OSMC 960 Cyclohexane 77 C₁₅H₁₉N₂OS MC 868 Cyclohexane 89 C₁₆H₁₇F₃N₂OS MC959 Cyclohexane 75 C₁₆H₁₇F₃N₂OS MC 952 Cyclohexane 69 C₁₆H₂₀N₂O₂S MC 957n-hexane/Cyclohexane 71 C₁₆H₂₀N₂O₂S MC 964 Cyclohexane 63 C₁₆H₂₀N₂O₂S MC1041 Cyclohexane 68 C₁₅H₂₀F₂N₂OS MC 1042 n-hexane 72 C₁₂H₂₂N₂OS MC877benzene 98 C₁₂H₂₀Cl₂N₂OS MC878 benzene 81 C₁₄H₁₄Cl₂N₂OS MC886cyclohexane 62 C₁₅H₁₆Cl₂N₂OS MC885 cyclohexane 56 C₁₅H₁₆Cl₂N₂OS MC815cyclohexane/benzene 55 C₁₅H₁₆Cl₂N₂OS MC888 cyclohexane 54 C₁₆H₁₆Cl₂N₂OSMC891 cyclohexane/benzene 49 C₁₇H₁₈Cl₂N₂OS MC871 benzene 95 C₁₂H₁₉F₂N₂OSMC860 cyclohexane 74 C₁₄H₁₄F₂N₂OS MC872 cyclohexane 46 C₁₅H₁₆F₂N₂OSMC866 cyclohexane 49 C₁₅H₁₆F₂N₂OS MC848 n-hexane/cyclohexane 48C₁₅H₁₆F₂N₂OS MC867 cyclohexane 45 C₁₆H₁₆FN₂OS MC870 cyclohexane 40C₁₇H₁₈F₂N₂OS MC1001 cyclohexane/benzene 52 C₁₃H₁₆Cl₂N₂OS MC996cyclohexane 45 C₁₇H₁₈Cl₂N₂OS MC1016 cyclohexane/benzene 42 C₁₆H20Cl₂N₂OSMC1000 diethyl ether 54 C16H₁₈Cl₂N₂OS MC1002 diethyl ether 40C₁₈H₂₀Cl₂N₂OS MC1003 cyclohexane 41 C₁₉H₂₂Cl₂N₂OS MC1007 cyclohexane 53C₁₅H₁₆F₂N₂OS MC1044 cyclohexane 49 C₁₆H₁₈F₂N₂OS MC1045 cyclohexane 58C₁₆H₁₈F₂N₂OS MC1110 n-hexane 75 C₁₆H₁₈F₂N₂OS MC1008 cyclohexane 60C₁₇H₁₈F₂N₂OS MC1013 benzene 44 C₁₈H₂₀F₂N₂OS MC1005 cyclohexane 40C₁₆H₁₈F₂N₂OS MC1006 cyclohexane 45 C₁₈H₂₀F₂N₂OS MC1014 cyclohexane 51C₁₉H₂₂F₂N₂OS MC971 n-hexane/cyclohexane 58 C₁₉H₂₀N₂OS MC972n-hexane/cyclohexane 49 C₂₁H₂₂N₂OS MC974 n-hexane 45 C₂₂H₂₄N₂OS MC969cyclohexane 54 C₂₀H₂₂N₂OS MC973 — 48 C₂₂H₂₄N₂OS MC975 n-hexane 41C₂₃H₂₆N₂OS MC844 cyclohexane 55 C₁₇H₂₂N₂OS MC845 n-hexane 61 C₁₇H₂₂N₂OSMC925 cyclohexane/benzene 88 C₁₆H₁₉N₃OS MC924 cyclohexane/benzene 100C₁₆H₁₉N₃O₃S MC909 cyclohexane 68 C₁₆H₁₉ClN₂OS MC910 cyclohexane 75C₁₆H₁₉ClN₂OS MC911 cyclohexane 79 C₁₆H₁₉ClN₂OS MC913 cyclohexane 65C₁₆H₁₉FN₂OS MC918 cyclohexane 72 C₁₆H₁₉FN₂OS MC919 cyclohexane 69C₁₆H₁₉FN₂OS MC912 benzene 93 C₁₈H₁₂Cl₂N₂OS MC914 cyclohexane/benzene 78C₁₅H₁₆Cl₂N₂OS MC920 cyclohexane 52 C₁₆H₁₈Cl₂N₂OS MC916 cyclohexane 63C₁₆H₁₈Cl₂N₂OS MC850 cyclohexane 53 C₁₆H₁₈Cl₂N₂OS MC915cyclohexane/benzene 49 C₁₇H₁₈Cl₂N₂OS MC917 cyclohexane 48 C₁₈H₂₀Cl₂N₂OSMC869 benzene 92 C₁₉H₁₂F₂N₂OS MC881 cyclohexane 76 C₁₃H₁₆F₂N₂OS MC905cyclohexane 65 C₁₆H₁₈F₂N₂OS MC921 cyclohexane 59 C₁₆H₁₈F₂N₂OS MC849n-hexane 49 C₁₆H₁₈F₂N₂OS MC922 cyclohexane 54 C₁₇H₁₈F₂N₂OS MC923cyclohexane 49 C₁₈H₂₀F₂N₂OS MC1060 cyclohexane/benzene 49 C₁₈H₁₄F₂N₂OSMC1109 cyclohexane 55 C₁₇H₂₀F₂N₂OS MC1047 cyclohexane 60 C₁₈H₂₀F₂N₂OSMC798 n-hexane 47 C₁₇H₂₂N₂OS MC1037 benzene 78 C₁₆H₁₈F₂N₂OS MC1038n-hexane/cyclohexane 62 C₁₇H₂₀F₂N₂OS MC804 cyclohexane 42 C₂₁H₂₄N₂OSMC1039 n-hexane 76 C₁₇H₂₀F₂N₂OS MC852 cyclohexane 68 C₁₆H₂₂N₂OS MC856n-hexane 42 C₂₁H₂₄N₂OS MC834 — 32 C₁₉H₂₆N₂OS MC1119 n-hexane/cyclohexane50 C₁₄H₁₄F₂N₃O MC1078 cyclohexane 49 C₁₄H₁₅F₂N₃O MC979 diethyl ether 58C₁₄H₁₅F₂N₃O MC980 cyclohexane/benzene 68 C₁₄H₁₆F₂N₃O MC1077 n-hexane 60C₁₅H₁₇F₂N₃O MC945 diethyl ether 80 C₁₅H₁₇F₂N₃O MC1043 acetonitrile 78C₁₄H₁₅F₂N₃O₂ MC1022 — 74 C₁₆H₁₃F₂N₃O MC1049 diethyl ether 45 C₁₇H₁₄F₂N₃OMC1048 — 48 C₁₇H₁₄F2N₃O MC1118 n-hexane 53 C₁₃H₁₇F₂N₃O MC1130 — 56C₁₆H₁₄F₂N₃O MC1050 n-hexane/cyclohexane 60 C₁₇H₁₄F₂N₃O MC1105cyclohexane/benzene 82 C₁₄H₁₇F₂N₃O MC1129 — 38 C₁₄H₂₁F₂N₃O MC1167acetonitrile 39 C₁₂H₁₁F₂N₃O MC1168 acetonitrile 48 C₁₃H₁₃F₂N₃O MC1186acetonitrile 62 C₁₃H₁₂F₂N₃O MC1185 acetonitrile 68 C₁₆H₁₄F₂N₃O MC1178acetonitrile 34 C₁₃H₁₃F₂N₃O MC1190 — 45 C₁₃H₁₇F₂N₃O MC1191 — 54C₁₅H₁₇F₂N₃O MC1189 — 55 C₁₆H₁₉F₂N₃O MC1192 — 59 C₁₆H₁₉F₂N₃O MC1180 — 62C₁₈H₂₁F₂N₃O MC1170 cyclohexane/benzene 34 C₁₄H₁₅F₂N₃O MC1187 — 49C₁₇H₂₁F₂N₃O MC1181 — 54 C₁₉H₂₃F₂N₃O MC1182 cyclohexane/benzene 88C₁₃H₁₃F₂N₃O MC1183 acetonitrile 84 C₁₆H₁₈F₂N₃O MC1188 acetonitrile 75C₁₅H₁₃F₂N₃O₂ MC1193 acetonitrile 78 C₁₅H₁₃F₂N₃OS MC1194 acetonitrile 68C₁₆H₁₇F₂N₃O MC1196 acetonitrile 52 C₁₅H₁₅F₂N₃O MC1202 acetonitrile 43C₁₅H17F₂N₃O MC1204 n-hexane 32 C₁₇H₂₁F₂N₃O MC1195 acetonitrile 80C₁₄H₁₃F₂N₃O MC1203 acetonitrile 62 C₁₇H₂₀F₂N₃O MC1205 acetonitrile 65C₁₆H₁₇F₂N₃O₂ MC1206 acetonitrile 54 C₁₆H₁₇F₂N₂OS MC1137n-hexane/cyclohexane 45 C₁₆H₁₈F₂N₂OS MC1175 n-hexane 51 C₁₇H₂₀F₂N₂OSMC1153 cyclohexane 58 C₁₇H₂₀F₂N₂OS MC1174 n-hexane/cyclohexane 48C₁₉H₂₂F₂N₂OS MC1161 cyclohexane/benzene 72 C₁₃H₁₂F₂N₂OS₂ MC1162cyclohexane/benzene 70 C₁₄H₁₄F₂N₂OS₂ MC1157 cyclohexane 69 C₁₅H₁₆F₂N₂OS₂MC1145 cyclohexane 62 C₁₆H₁₈F₂N₂OS₂ MC1140 n-hexane 64 C₁₃H₁₄N₂OS₂ ^(a)All compounds were analyzed for C, H, N, S, and, when required, Cl andF; analytical results were within ±0.4% of theroretical values.

TABLE 2 Cytotoxicity and anti-HIV-1 Activity of MC Compounds. (A)

^(a) [μM] Compd. X Y Z R R¹ R² R³ R⁴ R⁵ CC₅₀ ^(b) EC₅₀ ^(c) SI^(d) MC507 O H H 2,5-Me₂-c-hex H H H H H 143 3.5 40 MC 508 O H H 4,5-Me₂-c-hexH H H H H 58 6.4 9 MC 512 O H H 3,5-Me₂-c-hex H H H H H >200 30 >6.7 MC531 O Me H 2,5-Me₂-c-hex H H H H H 138 3.5 39 MC 1114 O H H sec-but F HH H F 130 25 52 MC 1103 O H H c-pent F H H H F >200 20 >10 MC 843 S H Hbenzoyloxy- H H H H H >200 45 >4 methyl MC 796 S H Ph sec-but H H H H H61 >61 — MC 890 S H Me iso-prop H H H H H >200 .9 >222 MC 892 S H Mec-pent H H H H H 159 .6 333 MC 898 S H Me c-hex H H H H H 149 .6 248 MC899 S H Et iso-prop H H H H H 200 .8 250 MC 900 S H Et c-pent H H H HH >200 1.0 >200 MC 903 S H Et c-hex H H H H H >200 1.3 >154 MC 806 S H Hsec-but Me H H H H >200 1.8 >111 MC 842 S H H c-pent Me H H H H >2003.4 >59 MC 809 S H H sec-but H H Me H H 200 0.6 333.3 MC 817 S H Hsec-but NO₂ H H H H >200 0.25 >800 MC 897 S H H sec-but H NO₂ H H H 1570.40 392 MC 863 S H H sec-but H H NO₂ H H 151 1.5 101 MC 854 S H Hsec-but Cl H H H H 200 1 200 MC 857 S H H sec-but H Cl H H H 116 2 58 MC859 S H H sec-but H H Cl H H 120 5 24 MC 880 S H H sec-but F H H H H 2000.26 769 MC 884 S H H sec-but H F H H H >200 0.7 >286 MC 889 S H Hsec-but H H F H H >200 8.7 23 MC 825 S H H sec-but NH₂ H H H H >20021.2 >9 MC 960 S H H sec-but H H NH₂ H H >200 23 >8 MC 868 S H H sec-butCF₃ H H H H >200 32 6.2 MC 959 S H H sec-but H H CF₃ H H 200 25 8 MC 952S H H sec-but OMe H H H H >200 1.96 >208 MC 957 S H H sec-but H OMe H HH >200 1.2 >166 MC 964 S H H sec-but H H OMe H H 147 14 10.5 MC 1041 S HH sec-but H F H H H >200 1.4 >143 MC 1042 S H H sec-but H Me H H H 1330.6 222 MC 877 S H H Me Cl H H H Cl >200 3.2 >62 MC 878 S H H iso-propCl H H H Cl >200 1.9 >105 MC 886 S H H n-but Cl H H H Cl >200 0.44 >454MC 885 S H H iso-but Cl H H H Cl >200 0.45 >444 MC 815 S H H sec-but ClH H H Cl >200 0.14 >1,428 MC 888 S H H c-pent Cl H H H Cl >200 0.4 >500MC 891 S H H c-hex Cl H H H Cl >200 0.6 >333 MC 871 S H H Me F H H H F200 0.81 247 MC 860 S H H iso-prop F H H H F >200 0.2 >1,000 MC 872 S HH n-but F H H H F 162 0.18 900 MC 866 S H H iso-but F H H H F 182 0.141,300 MC 848 S H H sec-but F H H H F 200 0.04 5,000 MC 867 S H H c-pentF H H H F >200 0.08 >2,500 MC 870 S H H c-hex F H H H F 200 0.08 2,500MC 1001 S H Me iso-prop Cl H H H Cl 117 1.2 97.5 MC 996 S H Me c-pent ClH H H Cl 78.3 1.0 78.3 MC 1016 S H Me c-hex Cl H H H Cl >200 2.9 >69 MC1000 S H Et iso-prop Cl H H H Cl >200 0.4 >500 MC 1002 S H Et c-pent ClH H H Cl 23.4 1.0 23.4 MC 1003 S H Et c-hex Cl H H H Cl >200 3.6 >55.5MC 1007 S H Me iso-prop F H H H F 167 0.05 3,340 MC 1044 S H Me iso-butF H H H F >200 0.05 >4,000 MC 1045 S H Me n-but F H H H F >200 0.072,857 MC 1110 S H Me sec-but F H H H F >200 0.03 >6,666 MC 1008 S H Mec-pent F H H H F >200 0.03 >6,666 MC 1013 S H Me c-hex F H H H F >2000.16 >1,250 MC 1005 S H Et iso-prop F H H H F 70 0.08 875 MC 1006 S H Etc-pent F H H H F 200 0.15 1,333 MC 1014 S H Et c-hex F H H H F 130 0.052,600 MC 971 S H Me iso-prop CH═CH—CH═CH H H H 119 1.1 108 MC 972 S H Mec-pent CH═CH—CH═CH H H H 93 0.5 186 MC 974 S H Me c-hex CH═CH—CH═CH H HH 45 0.14 321.4 MC 969 S H Et iso-prop CH═CH—CH═CH H H H 50 1.5 33.3 MC973 S H Et c-pent CH═CH—CH═CH H H H 51 3.0 17 MC 975 S H Et c-hexCH═CH—CH═CH H H H 16.9 0.18 94 MC 844 S Me H sec-but Me H H H H >2001.7 >118 MC 845 S Me H sec-but H H Me H H 26 0.8 32 MC 925 S Me Hsec-but H NO₂ H H H >200 0.35 >571 MC 924 S Me H sec-but H H NO₂ HH >200 2 >100 MC 909 S Me H sec-but Cl H H H H >200 0.27 >741 MC 910 SMe H sec-but H Cl H H H >200 0.96 >208 MC 911 S Me H sec-but H H Cl HH >200 9.5 20 MC 913 S Me H sec-but F H H H H 140 0.41 341 MC 918 S Me Hsec-but H F F H H >200 1.2 >166 MC 919 S Me H sec-but H H H H H 105 119.5 MC 912 S Me H Me Cl H H H Cl >200 3.2 >62 MC 914 S Me H iso-prop ClH H H Cl >200 1.3 >154 MC 920 S Me H n-but Cl H H H Cl >200 1.17 >171 MC916 S Me H iso-but Cl H H H Cl >200 1.2 >166 MC 850 S Me H sec-but Cl HH H Cl >200 0.05 >4,000 MC 915 S Me H c-pent Cl H H H Cl >200 1.8 >111MC 917 S Me H c-hex Cl H H H Cl >200 22 >9 MC 869 S Me H Me F H H H F200 0.19 1,053 MC 881 S Me H iso-prop F H H H F >200 0.05 >4,000 MC 905S Me H n-but F H H H F >200 0.08 >2,500 MC 921 S Me H iso-but F H H H F64 0.1 640 MC 849 S Me H sec-but F H H H F 80 0.001 8,000 MC 922 S Me Hc-pent F H H H F >200 0.08 >2,500 MC 923 S Me H c-hex F H H H F >2000.09 >2,222 MC 1060 S Me Me Me F H H H F >200 0.04 >5,000 MC 1109 S MeMe sec-but F H H H F 200 0.03 >6,666 MC 1047 S Me Me c-pent F H H HF >200 0.009 >22,222 MC 798 S Et H sec-but H H H H H >200 1.0 >200 MC1037 S Et H iso-prop F H H H F 65 0.2 326 MC 1038 S Et H sec-but F H H HF >200 0.1 >2,000 MC 804 S Et H sec-but CH═CH—CH═CH H H H >200 5.3 >34MC 1039 S iso-prop H iso-prop F H H H F >200 0.4 >500 MC 852 S allyl Hsec-but H H H H H >200 3 >67 MC 856 S n-prop H sec-but H H H H H 190 1216 MC 834 S n-but H sec-but H H H H H >200 >200 — MC 1119 NH H H ethyl FH H H F >200 0.8 >250 MC 1078 NH H H n-prop F H H H F 200 0.11 1,818 MC979 NH H H iso-prop F H H H F >200 0.38 >526 MC 980 NH H H c-prop F H HH F >200 3.17 >63 MC 1077 NH H H n-but F H H H F 100 0.10 1,000 MC 945NH H H sec-but F H H H F >200 0.13 >1,540 MC 1043 NH H H MeOethyl F H HH F >200 0.8 >250 MC 1022 NH H H c-pent F H H H F >200 0.09 >2,222 MC1049 NH H H c-hex F H H H F 66 0.14 471 MC 1048 NH H Me c-pent F H H H F75 0.03 2,500 MC 1118 NH Me H iso-prop F H H H F 190 0.03 6,333 MC 1130NH Me H sec-but F H H H F 200 0.07 2,857 MC 1050 NH Me H c-pent F H H HF >200 0.02 >10,000 MC 1105 NH Me H benzyl F H H H F 50 0.50 100 MC 1129NH Me H c-pent F H H H F 90 0.02 4,500 MC 1167 NH H H Me F H H H F >2001.5 >133 MC 1168 NH Me H Me F H H H F 135 0.4 335 MC 1186 NH Me H n-propF H H H F >200 0.02 >10,000 MC 1185 NH Me H n-but F H H H F >2000.02 >10,000 MC 1178 NH H Me Me F H H H F 106 0.11 964 MC 1190 NH H Men-prop F H H H F 103 0.02 5,150 MC 1191 NH H Me iso-prop F H H H F 1150.03 3,830 MC 1189 NH H Me n-but F H H H F 52 0.03 1,730 MC 1192 NH H Mesec-but F H H H F 86 0.04 2,150 MC 1180 NH H Me c-hex F H H H F 56 0.022,545 MC 1170 NH Me Me Me F H H H F 200 0.03 >6,666 MC 1187 NH Me Men-but F H H H F 83 0.01 8,300 MC 1181 NH Me Me c-hex F H H H F 58 0.032,231 MC 1182 N H H Me₂ F H H H F >200 0.05 >4,000 MC 1183 N H HMe-piperaz F H H H F >200 7.1 >28 MC 1188 N H H morph F H H H F >2000.6 >333 MC 1193 N H H thiomorph F H H H F >200 0.05 >4,000 MC 1194 N HH piperid F H H H F >200 0.02 >10,000 MC 1196 N H H pyrrolid F H H HF >200 2.1 >95 MC 1202 N H H Et₂ F H H H F >200 0.26 >769 MC 1204 N H H(n-prop)₂ F H H H F >200 3.8 >53 MC 1195 N Me H Me₂ F H H H F >2000.02 >10,000 MC 1203 N Me H Me-piperaz F H H H F >200 0.36 >555 MC 1205N Me H morph F H H H F >200 0.047 >4,255 MC 1206 N Me H thiomorph F H HH F >200 0.09 >2,222 MC 1137 S Me Me iso-prop F H H H F 200 0.007 28,571MC 1175 S Me Me n-but F H H H F 112 0.008 14,000 MC 1153 S Me Me iso-butF H H H F >200 0.01 >20,000 MC 1174 S Me Me c-hex F H H H F >2000.018 >11,111 MC 1047+ S Me Me c-pent F H H H F >200 0.002 >100,000 MC1047− S Me Me c-pent F H H H F >200 0.7 >286 MC 1161 S H H MeSMe F H H HF >200 0.80 >250 MC 1162 S Me H MeSMe F H H H F 30 0.12 250 MC 1157 S EtH MeSMe F H H H F 50 0.11 454 MC 1145 S iso-prop H MeSMe F H H H F 2000.10 2,000 MC 1140 S H H MeSMe H H H H H >200 20 >10 ^(a)Data representmean values of at least two separate experiments. ^(b)Compound doserequired to reduce the viability of mock-infected cells by 50%, asdetermined by the MMT method. ^(c)Compound dose required to achieve 50%protection of MT-4 cells from HIV-1 induced cytopathogenicity, asdetermined by the MTT method. ^(d)Selectivity index, CC₅₀/EC₅₀ ratio.

What is claimed is:
 1. A compound of the formula:

wherein: a) X is —NK; b) R is —C₁₋₄alkyl optionally substituted by oneor more of heteroatoms selected from O, S, and N, —C₃₋₆cycloalkyloptionally substituted by one or more of heteroatoms selected from O, S,and N, -aryl, arylalkyl, or heterocycle; c) Y is —H, —C₁₋₄alkyl, or—C₃₋₆cycloalkyl; d) Z is —C₁₋₄alkyl, or —C₃₋₆cycloalkyl; e) R₁ is —H,—C₁₋₄alkyl, halogen, —NO₂, —OW, or —SW; f) R₂ is —H, —C₁₋₄alkyl,-halogen, —NO₂, —OW, or —SW; g) R₃ is —H, —C₁₋₄alkyl, -halogen, —NO₂,—OW, or —SW; h) R₄ is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW, or —SW; i) R₅is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW, or —SW; j) K is —H, —C₁₋₄alkyl,or —C₃₋₆cycloalkyl; and k) W is —H, —CH₃, or -aryl; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1wherein: X = NH Y = H Z = CH₃ R = cPe R₁ = F R₂ = H R₃ = H R₄ = H R₅ =F; X = NH Y = CH₃ Z = CH₃ R = cPe R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X= NH Y = H Z = CH₃ R = CH_(3R) ₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = NHY = H Z = CH₃ R = nPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = NH Y = H Z= CH₃ R = iPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = NH Y = H Z = CH₃ R= nBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = NH Y = H Z = CH₃ R = sBuR₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = NH Y = H Z = CH₃ R = cHex R₁ = FR₂ = H R₃ = H R₄ = H R₅ = F; X = NH Y = CH₃ Z = CH₃ R = CH₃ R₁ = F R₂ =H R₃ = H R₄ = H R₅ = F; X = NH Y = CH₃ Z = CH₃ R = nBu R₁ = F R₂ = H R₃= H R₄ = H R₅ = F; or X = NH Y = CH₃ Z = CH₃ R = cHex R₁ = F R₂ = H R₃ =H R₄ = H R₅ = F; and

further wherein cPe is cyclopentyl, nPr is n-propyl, iPr is isopropyl,nBu is n-butyl, sBu is sec-butyl, and cHex is cyclohexyl.
 3. Thecompound of claim 1 wherein X is —NK.
 4. The compound of claim 1wherein: a) X is —NK; and b) K is —H or —C₁₋₄alkyl.
 5. The compound ofclaim 1 wherein: a) X is —NK; b) R is —C₁₋₄alkyl or —C₃₋₆cycloalkyl,optionally substituted by one or more of heteroatoms selected from O, S,and N; and c) K is —H or —C₁₋₄alkyl.
 6. The compound of claim 1 wherein:a) X is —NK; b) R is —C₁₋₄alkyl or —C₃₋₆cycloalkyl; and c) K is —H or—C₁₋₄alkyl.
 7. The compound of claim 1 wherein: a) X is —NK; b) Y is—C₁₋₄alkyl; c) Z is —C₁₋₄alkyl; d) R₁ is halogen; e) R₂ is —H; f) R₃ is—H; g) R₄ is —H; and h) R₅ is -halogen.
 8. The compound of claim 1wherein: a) X is —NK; b) K is —H or —C₁₋₄alkyl; c) Y is —C₁₋₄alkyl; d) Zis —C₁₋₄alkyl; e) R₁ is halogen; f) R₂ is —H; g) R₃ is —H; h) R₄ is —H;and i) R₅ is -halogen.
 9. The compound of claim 1 wherein: a) X is —NK;b) R is —C₁₋₄alkyl or —C₃₋₆cycloalkyl, optionally substituted by one ormore of heteroatoms selected from O, S, and N; c) K is —H or —C₁₋₄alkyl;d) Y is —C₁₋₄alkyl; e) Z is —C₁₋₄alkyl; f) R₁ is halogen; g) R₂ is —H;h) R₃ is —H; i) R₄ is —H; and j) R₅ is -halogen.
 10. The compound ofclaim 1 wherein: a) X is —NK; b) R is —C₁₋₄alkyl or —C₃₋₆cycloalkyl; c)K is —H or —C₁₋₄alkyl; d) Y is —C₁₋₄alkyl; e) Z is —C₁₋₄alkyl; f) R₁ ishalogen; g) R₂ is —H; h) R₃ is —H; i) R₄ is —H; and j) R₅ is -halogen.11. The compound of claim 1 wherein X is NH, Y is CH₃, Z is CH₃, R iscyclopentyl, R₁ is F, R₂ is H, R₃ is H, R₄ is H, and R₅ is F.
 12. Apharmaceutical composition comprising the compound of claim 1 and apharmaceutically acceptable carrier.
 13. A pharmaceutical compositioncomprising the compound of claim 3 and a pharmaceutically acceptablecarrier.
 14. A pharmaceutical composition comprising the compound ofclaim 11 and a pharmaceutically acceptable carrier.
 15. A process forpreparing a compound of claim 1 wherein X is —NK comprising reacting aS-methyl(5-alkyl)-6-benzyl(substituted)-2-thiouracil with an amine. 16.A method of treating infection by HIV or of treating AIDS, comprisingadministering to a mammal an effective amount of a compound of claim 1,wherein X is —NK.
 17. The method of claim 16 wherein: a) X is —NK; b) Ris —C₁₋₄alkyl or —C₃₋₆cycloalkyl; and c) K is —H or —C₁₋₄alkyl.
 18. Themethod of claim 16 wherein: a) X is —NK; b) R is —C₁₋₄alkyl or—C₃₋₆cycloalkyl; c) K is —H or —C₁₋₄alkyl; d) Y is —C₁₋₄alkyl; e) Z is—C₁₋₄alkyl; f) R₁ is halogen; g) R₂ is —H; h) R₃ is —H; i) R₄ is —H; andj) R₅ is -halogen.
 19. A compound of the formula:

wherein: a) X is —NK; b) R is —C₁₋₄alkyl optionally substituted by oneor more of heteroatoms selected from O, S, and N, —C₃₋₆cycloalkyloptionally substituted by one or more of heteroatoms selected from O, S,and N, -aryl, arylalkyl, or heterocycle; c) Y is —C₁₋₄alkyl, or—C₃₋₆cycloalkyl; d) Z is —H, —C₁₋₄alkyl, or —C₃₋₆cycloalkyl; e) R₁ is—H, —C₁₋₄alkyl, halogen, —NO₂, —OW, or —SW; f) R₂ is —H, —C₁₋₄alkyl,-halogen, —NO₂, —OW, or —SW; g) R₃ is —H, —C₁₋₄alkyl, -halogen, —NO₂,—OW, or —SW; h) R₄is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW, or —SW; i) R₅is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW, or —SW; j) K is —H, —C₁₋₄alkyl,or —C₃₋₆cycloalkyl; and k) W is —H, —CH₃, or -aryl; or apharmaceutically acceptable salt thereof.
 20. The compound of claim 19wherein: X = NH Y = CH₃ Z = H R = iPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ =F; X = NH Y = CH₃ Z = H R = sBu R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X =NH Y = CH₃ Z = H R = cPe R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = NH Y =CH₃ Z = H R = benz R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = NH Y = CH₃ Z= H R = CH₃ R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = NH Y = CH₃ Z = H R =nPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = NH Y = CH₃ Z = H R = nBu R₁= F R₂ = H R₃ = H R₄ = H R₅ = F; or X = NCH₃ Y = CH₃ Z = H R = CH₃ R₁ =F R₂ = H R₃ = H R₄ = H R₅ = F;

and further wherein cPe is cyclopentyl, nPr is n-propyl, iPr isisopropyl, nBu is n-butyl, sBu is sec-butyl, and benz is benzyl.
 21. Acompound of the formula:

wherein: a) X is —NK; b) R is —C₁₋₄alkyl optionally substituted by oneor more of heteroatoms selected from O, S, and N, —C₃₋₆cycloalkyloptionally substituted by one or more of heteroatoms selected from O, S,and N, -aryl, arylalkyl, or heterocycle; c) Y is H, —C₁₋₄alkyl, or—C₃₋₆cycloalkyl; d) Z is —H, —C₁₋₄alkyl, or —C₃₋₆cycloalkyl; e) R₁ is—C₁₋₄alkyl, halogen, —NO₂, —OW, or —SW; f) R₂ is —H, —C₁₋₄alkyl,-halogen, —NO₂, —OW, or —SW; g) R₃ is —H, —C₁₋₄alkyl, -halogen, —NO₂,—OW, or —SW; h) R₄ is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW, or —SW; i) R₅is —H, —C₁₋₄alkyl, -halogen, —NO₂, —OW, or —SW; j) K is —H, —C₁₋₄alkyl,or —C₃₋₆cycloalkyl; and k) W is —H, —CH₃, or -aryl; or apharmaceutically acceptable salt thereof.
 22. The compound of claim 21wherein: X = NH Y = H Z = H R = Et R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X= NH Y = H Z = H R = nPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = NH Y =H Z = H R = iPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = NH Y = H Z = H R= cPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = NH Y = H Z = H R = nBu R₁= F R₂ = H R₃ = H R₄ = H R₅ = F; X = NH Y = H Z = H R = sBu R₁ = F R₂ =H R₃ = H R₄ = H R₅ = F; X = NH Y = H Z = H R = MeOEt R₁ = F R₂ = H R₃ =H R₄ = H R₅ = F; X = NH Y = H Z = H R = cPe R₁ = F R₂ = H R₃ = H R₄ = HR₅ = F; X = NH Y = H Z = H R = cHex R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F;X = NH Y = H Z = H R = CH₃ R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = NCH₃Y = H Z = H R = CH₃ R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = NEt Y = H Z= H R = Et R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; or X = NnPr Y = H Z = H R= nPr R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F;

and further wherein Et is ethyl, cPe is cyclopentyl, nPr is n-propyl,iPr is isopropyl, cPr is cyclopropyl, nBu is n-butyl, sBu is sec-butyl,and cHex is cyclohexyl.
 23. A compound of the formula:

wherein: X = N Y = CH₃ Z = H R = Me-Pip R₁ = F R₂ = H R₃ = H R₄ = H R₅ =F; X = N Y = CH₃ Z = H R = Morph R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X =N Y = CH₃ Z = H R = S-morp R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = N Y =H Z = H R = Me-Pip R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = N Y = H Z = HR = Morph R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = N Y = H Z = H R =S-morp R₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; X = N Y = H Z = H R = PiperR₁ = F R₂ = H R₃ = H R₄ = H R₅ = F; or X = N Y = H Z = H R = Pyrroli R₁= F R₂ = H R₃ = H R₄ = H R₅ = F, and

further wherein Me-Pip is methylpiperidinyl, Morph is morpholinyl,S-morp is thiomorpholinyl, Piper is piperidinyl, and pyrroli ispyrrolidinyl.
 24. The pharmaceutical composition of claim 12 in the formof an orally-administratable tablet.
 25. The pharmaceutical compositionof claim 12 in the form of an orally-administratable suspension.
 26. Thepharmaceutical composition of claim 12 in the form of a nasal spray. 27.The pharmaceutical composition of claim 12 in the form of a sterileinjectable preparation.
 28. A pharmaceutical composition comprising thecompound of claim 19 and a pharmaceutically acceptable carrier.
 29. Thepharmaceutical composition of claim 28 in the form of anorally-administratable tablet.
 30. The pharmaceutical composition ofclaim 28 in the form of an orally-administratable suspension.
 31. Thepharmaceutical composition of claim 28 in the form of a nasal spray. 32.The pharmaceutical composition of claim 28 in the form of a sterileinjectable preparation.
 33. A pharmaceutical composition comprising thecompound of claim 21 and a pharmaceutically acceptable carrier.
 34. Thepharmaceutical composition of claim 33 in the form of anorally-administratable tablet.
 35. The pharmaceutical composition ofclaim 33 in the form of an orally-administratable suspension.
 36. Thepharmaceutical composition of claim 33 in the form of a nasal spray. 37.The pharmaceutical composition of claim 33 in the form of a sterileinjectable preparation.
 38. A pharmaceutical composition comprising thecompound of claim 23 and a pharmaceutically acceptable carrier.
 39. Thepharmaceutical composition of claim 38 in the form of anorally-administratable tablet.
 40. The pharmaceutical composition ofclaim 38 in the form of an orally-administratable suspension.
 41. Thepharmaceutical composition of claim 38 in the form of a nasal spray. 42.The pharmaceutical composition of claim 38 in the form of a sterileinjectable preparation. 43.2-Cyclopentylamino-6-{1-(2,6-difluorophenyl)ethyl}-3,4-dihydro-5-methylpyrimidin-4-(3H)-one.44. A method of treating infection by HIV or of treating AIDS,comprising administering to a mammal an effective amount of a compoundof claim
 43. 45. A pharmaceutical composition comprising the compound ofclaim 43 and a pharmaceutically acceptable carrier.
 46. Thepharmaceutical composition of claim 45 in the form of anorally-administratable tablet.
 47. The pharmaceutical composition ofclaim 46 in the form of an orally-administratable suspension.
 48. Thepharmaceutical composition of claim 46 in the form of a nasal spray. 49.The pharmaceutical composition of claim 46 in the form of a sterileinjectable preparation.